Disease relevance of Egr1

• Here we have assessed the effect of Egr1 deficiency on tumor development in two transgenic mouse models of prostate cancer (CR2-T-Ag and TRAMP) [1].
• These results indicate a unique role for Egr1 in regulating the transition from localized, carcinoma in situ to invasive carcinoma [1].
• Analysis of these genes reveals a consensus promoter structure consisting of multiple, often closely spaced c-Myc binding sites and three additional Wilm's tumor and Egr1-like motifs [2].
• In contradiction, in breast, lung and brain tumors, Egr1 expression is often absent or reduced and when re-expressed, results in growth suppression [3].
• Luteinizing hormone deficiency and female infertility in mice lacking the transcription factor NGFI-A (Egr-1) [4].
• This study provides what we believe is the first evidence that Egr-1 increases the mortality of HSV-1 encephalitis by enhancing viral replication [5].

Psychiatry related information on Egr1

• To evaluate whether this transcription factor is directly involved in activity-dependent plasticity, mice lacking Egr1 were deprived of the use of one eye during the developmental critical period [postnatal day 24 (P24)-P34] [6].
• Dietary administration of YKD resulted in significant modulation of Egr1, Grp78, Hsp86, SOD1, and alphaB crystallin mRNA expression and a trend toward increased exploratory behavior in older mice [7].
• In situ hybridization showed that after injecting muscimol in the D2R-/- mice, the expression of enkephalin and immediate early gene, NGFI-A, was closely regulated with the locomotor activity regulated by GABAergic stimulation [8].

High impact information on Egr1

• One cDNA clone of a primary response gene, expressed upon macrophage differentiation, encoded for Egr-1, a zinc finger transcription factor [9].
• Egr-1 antisense oligomers in the culture media blocked macrophage differentiation in both myeloid leukemia cell lines and normal myeloblasts [9].
• HL-60 cells constitutively expressing an Egr-1 transgene (HL-60Egr-1) could be induced for macrophage, but not granulocyte, differentiation [9].
• The Egr-1 gene was observed to be transcriptionally silent in HL-60 cells, but active in U-937 and M1 cells, the latter two being predetermined for macrophage differentiation [9].
• These observations indicate that expression of Egr-1 is essential for and restricts differentiation of myeloblasts along the macrophage lineage [9].

Chemical compound and disease context of Egr1

• The results provide a mechanistic basis for the oncogenic role of Egr1 in TRAMP C2 prostate cancer cells [10].
• This forms a foundation for analysis of detailed mechanisms underlying Egr-1 activation during hyperoxia and understanding its consequences for regulating cell response to oxygen toxicity [11].
• CONCLUSIONS: Differential regulation of Egr-1 expression by insulin and glucose in vascular cells may be one of the initial key events that plays a crucial role in the development of diabetic vascular complications [12].
• We investigated the combined use of Ad.Egr-TNF, a replication-defective adenoviral vector encoding the cDNA for TNF-alpha under the control of chemo-inducible elements of the egr1 gene promoter, and intraperitoneal temozolomide in an intracranial human malignant glioma model [13].
• Administration of carbachol, noradrenaline, and bradykinin induced Egr-1 mRNA expression within 1 h in mouse neuroblastoma x rat glioma hybrid NG108-15 cells [14].

Biological context of Egr1

• In Med23-/- cells, histone acetylation, methylation, and chromatin remodeling complex association at the Egr1 promoter were equivalent to that of wild-type cells, yet Egr1 induction was greatly reduced [15].
• Using a novel adaptation of the yeast two-hybrid screen, we have identified several point mutations in NAB corepressors that interfere with their ability to bind to the Egr1 R1 domain [16].
• Early growth response (Egr) transcription factors (Egr1 to Egr4) are synaptic activity-inducible immediate early genes (IEGs) that regulate some aspects of synaptic plasticity-related to learning and memory, yet the target genes regulated by them are unknown [17].
• Egr1 regulates luteinizing hormone beta subunit (LHbeta) gene expression in the pituitary gland [18].
• In particular, Egr1 is essential for persistence of late-phase long-term potentiation (L-LTP), for hippocampus-dependent long-term memory formation, and for reconsolidation of previously established memories [17].

Anatomical context of Egr1

• Stringent expression analysis revealed 266 transcripts with >2-fold differential expression in Egr1-null mouse embryo fibroblasts, including 143 known genes [19].
• We have found that on TCR transgenic backgrounds, Egr1-deficient mice have a reduction in their number of naive T cells [20].
• Furthermore, gel-shift analyses demonstrated the binding of Egr1, 2, and 3 in Th2 cells and Egr1 and 2, but not Egr3 in Th1 cells at a known Egr site [21].
• The induction of Egr1 by external stimuli is generally transient but appears to be sustained in some prostate tumor cell lines and tumors, suggesting that Egr1 stimulates tumor cell growth [3].
• Activity-dependent activation of Egr1 has been reported in forebrain regions, including the anterior cingulate cortex (ACC), after peripheral injury [22].

Associations of Egr1 with chemical compounds

• The results show that the Egr1 promoter is induced by cisplatin and that this induction is mediated in part through the CArG elements [23].
• Functional compensation by Egr4 in Egr1-dependent luteinizing hormone regulation and Leydig cell steroidogenesis [18].
• Due to decreased levels of LHbeta, female Egr1-deficient mice are anovulatory, have low levels of progesterone, and are infertile [18].
• In wild-type mice, challenge with LPS increased Egr-1 messenger RNA (mRNA) and DNA binding activity in liver; this response to LPS was enhanced after chronic ethanol feeding [24].
• Transient expression of Egr-3 alone increased fasL promoter activity in a cyclosporin A-insensitive manner, whereas expression of Egr-1 had little effect [25].

Physical interactions of Egr1

• Protein kinase casein kinase II (CK2) phosphorylates Egr-1 and prevents its binding to Sp1 [26].
• The factors binding to the serum response elements of the Egr1 promoter form a ternary complex (TC) consisting of serum response factor and either Elk-1 or serum response factor accessory protein-1a [27].
• A Krox binding site regulates protease nexin-1 promoter activity in embryonic heart, cartilage and parts of the nervous system [28].
• In addition, mutagenesis of the Egr-1 binding site within the CCN1 promoter completely blunted the stretch-induced activation of the promoter [29].
• An electrophoretic mobility shift assay demonstrated that Egr-1 bound to the proximal promoter of the Mn-SOD gene in response to PDGF [30].

Regulatory relationships of Egr1

• NGFI-A apparently influences female reproductive capacity through its regulation of LH-beta transcription [4].
• Interestingly, EGR-1 is shown to down-regulate the transcription of its own gene expression, whereas Sp1 activated Egr-1 gene expression [31].
• Egr-1 activates the LHbeta gene in vitro through synergy with steroidogenic factor-1 (SF-1), a protein required for gonadotrope function [32].
• In vitro studies suggest that Egr-1 is capable of regulating the expression of tumor necrosis factor-alpha (TNF-alpha) and other genes involved in airway inflammation and reactivity following allergen stimulation [33].
• Transcriptional activity of Egr-1 protein was enhanced by GnRH treatment [34].
• Egr-1 increased the transcriptional activation of Areas I and II, despite the absence of Egr-1 recognition sequences within this promoter segment, suggesting that Egr-1 also can regulate the pdx-1 promoter indirectly [35].

Other interactions of Egr1

• An analysis of NGFI-A-deficient mice derived from embryonic stem cells demonstrated female infertility that was secondary to LH-beta deficiency [4].
• In contrast, high-passage EGR1-null MEFs retain the WT p53 sequence but with much reduced expression, remain untransformed, and grow continuously [36].
• Full stimulation of anergic A.E7 T cells fails to enhance IL-2 and Egr-1 expression, whereas Egr-2 expression is greatly increased [37].
• Although other Egr proteins are expressed in LbetaT2 cells and are capable of interacting with SF-1, GnRH stimulation of Egr-1 was the most robust [32].
• An early growth response protein (Egr) 1 cis-element is required for gonadotropin-releasing hormone-induced mitogen-activated protein kinase phosphatase 2 gene expression [34].
• Enhanced injury in egr-1-/- mice was associated with reduced tumor necrosis factor (TNF)alpha mRNA and protein expression, reduced Akt phosphorylation and nuclear localization of NFkappaB-p65 in nuclei of cells in the hepatic sinusoid [38].

Analytical, diagnostic and therapeutic context of Egr1

• Electrophoretic mobility shift assay as well as chromatin immunoprecipitation confirmed that p53 is a direct target of Egr1 [19].
• Egr1 regulation of these genes, identified by Affymetrix microarray, was confirmed by real-time PCR, immunoblot, and chromatin immunoprecipitation assays [10].
• A cDNA array identified the transcription factor early growth response factor 1 (Egr1) as a target gene for TGFbeta in late phases of the wound healing process [39].
• Immunocytochemistry indicated that Egr-1 was expressed prominently in the smooth muscle-actin positive cells, particularly in areas of macrophage infiltration, and in other cell types, including endothelial cells [40].
• Expression of Egr-1 was an average of 5-fold higher in the lesion than in the adjacent media, a result confirmed by RT-PCR, and many Egr-1-inducible genes were also strongly elevated in the lesion [40].

References